: The involvement of major neurotransmitter systems in schizophrenia and possibly other neuropsychiatric disorders or traits, can be evaluated in part by direct examination of candidate genes. This application utilizes a candidate gene-base, genetic epidemiology approach to explore the possible role genes in the serotonin (5- hydroxytryptophan; 5-HT) system and in the N- methyl-D-aspartate (NMDA) receptor complex in the etiology of schizophrenia. The proposed study design does not utilize either linkage analysis nor linkage disequilibrium-based association strategies, both of which can be problematic when applied to non- Mendelian, multifactorial diseases such as schizophrenia. Instead, the strategy first involves the identification of DNA sequence variants of likely functional significance in genes involved in the serotonin pathway or in the NMDA receptor complex. Subsequently, these variant alleles will be tested for an association with schizophrenia or other neuropsychiatric disorders. More specifically, candidate genes will be examined in subset of schizophrenics by molecular genetics methods for rapidly detecting DNA sequence change (dideoxy fingerprinting, a variant of single strand conformation polymorphism analysis, and direct genomic sequencing) in search of sequence variants that are of likely functional significance will be examined for an association with schiz- ophrenia. As allele frequencies often vary by ethnic background, the use of a control group that is ethically-matched to cases is imperative in these analyses to prevent spurious associations. The proposed control group will consist of the parents of cases; that is, the cases group will be comprised of the transmitted parental alleles and the control group will be comprised of the nontransmitted parental alleles (genotype relative risk analysis). For sequence changes of likely functional significance that are tested but not found to be associated with schizophrenia, genotype-to-phenotype studies, utilizing the unique epidemiological resource of the Mayo Clinic, will be per- formed to determine if another neuropsychiatric disease or trait is associated with the variant allele. If suggestive evidence is found, further evaluations, including family- bases studies, will be conducted.